Multi-Modal Gene Therapy For Pancreatic Cancer Using Targeted Nanovectors Pancreatic cancer is associated with very poor prognosis partly due to rapid invasion and metastasis Novel clinically-translatable therapeutic strategies are necessary in order to effectively treat advanced stage pancreatic cancer. Although several gene therapy strategies have been tried, the major limitation is in the development of safe and effective delivery system for systemic administration. To overcome systemic gene delivery challenges, we have developed novel non-condensing gelatin based engineered nanovector systems (GENS) that can encapsulate plasmid DNA, protect against degradation in the systemic circulation and during intracellular transport, and efficiently transfect in vitro and in vivo in an orthotopic human breast tumor xenograft model. The expressed soluble Flt-1 (VEGF-R1) was therapeutically effective in the treatment of orthotopic human breast adenocarcinoma. Based on these impressive preliminary observations, we propose to use epidermal growth factor receptor (EGFR)-targeted long-circulating GENS encapsulated with wt-p53 and sFlt-1 encoding plasmids for single and combination gene therapy in pancreatic cancer. EGFR is over-expressed in approximately 50% pancreatic cancer and is a predictive indicator of tumor metastasis and resistance to chemo- and radio-therapy. Our hypothesis is that wt-p53 transfection will suppress tumor growth, induce apoptosis, and provide the bystander effect, while the expressed sFlt-1 will lead to anti-angiogenic effect and prevent secondary metastasis. This combination therapy, delivered with safe EGFR-targeted GENS, will be especially beneficial in advanced stages of pancreatic cancer without the harmful side effects. The specific aims of this proposal are to: (1) formulate, using engineering design criteria, EGFR-targeted GENS for systemic p53 and sFlt-1 gene delivery; (2) evaluate uptake, cytotoxicity, and transfection in pancreatic adenocarcinoma (Panc-1 and Capan-1) cells; (3) examine the biodistribution, tumor uptake, and transfection in pancreatic adenocarcinoma-bearing nude mice upon systemic administration; (4) examine the therapeutic efficacy and prevention of metastasis in subcutaneous and orthotopic pancreatic adenocarcinoma-bearing nude mice, and (5) determine acute safety profile of systemically administered GENS. The results from this study are critical in order to adapt this clinically-translatable technology into the clinic for benefit to pancreatic cancer patients in the near future.